1. A method for alerting an aircraft crew member of a potential conflict between a first aircraft and a second aircraft on a first taxiway, the method comprising the steps of:
supplying, to a processor disposed in the first aircraft, data related to real-time positioning the first aircraft on the first taxiway;
transmitting, from the second aircraft to the first aircraft, data related to real-time positioning of the second aircraft;
supplying, to the processor, the data related to real-time positioning of the second aircraft;
processing, in the processor, the data related to real-time positioning of the second aircraft, to predict whether the second aircraft will enter the first taxiway, and
supplying display commands to a display disposed in the first aircraft that cause the display to render the first taxiway as a plurality of segments and, if the processor predicts that the second aircraft will enter the first taxiway, that cause the display to change an appearance of the segment of the first taxiway on which the first aircraft is located.
2. The method of claim 1, wherein the step of transmitting comprises transmitting from an automatic dependent surveillance broadcast transmitter disposed in the second aircraft.
3. The method of claim 1, wherein the method further comprises:
processing the data related to real-time positioning the first aircraft to identify the segment on which the first aircraft is located;
processing data related to real-time positioning the second aircraft to identify the segment on which the second aircraft is positioned;
comparing, in the processor, the segment on which the first aircraft is located and the segment on which the second aircraft is positioned; and
predicting that the potential conflict exists, when the segment on which the first aircraft is located and the segment on which the second aircraft is positioned are located relative to each other such that the first aircraft is not provided with an egress from the first taxiway.
4. The method of claim 1, wherein the step of processing comprises:
calculating a turning radius of the second aircraft from the real-time positioning data of the second aircraft;
projecting a predicted path of the second aircraft from the calculated turning radius; and
predicting that the potential conflict exists, based on the predicted path.
5. The method of claim 4, wherein the method further comprises:
processing the data related to real-time positioning the first aircraft to identify the segment on which the first aircraft is located;
processing the data related to real-time positioning the second aircraft to determine whether the predicted path indicates the second aircraft will travel on the first taxiway;
if the predicted path indicates the second aircraft will travel on the first taxiway, assigning the second aircraft with a segment of the first taxiway closest to the second aircraft;
comparing the segment on which the first aircraft is located and the segment on which the second aircraft is positioned; and
predicting that the potential conflict exists, when the segment on which the first aircraft is located and the segment on which the second aircraft is positioned are located relative to each other such that the first aircraft is not provided with an egress from the first taxiway.
6. The method of claim 1, wherein the segment of the first taxiway has a first color and changing the appearance of the segment comprises changing the segment of the first taxiway to a second color.
7. The method of claim 6, wherein changing the appearance comprises flashing the segment of the first taxiway.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A conjugate of the formula I:
B is a bio-compatible polymer moiety optionally covalently attached to a branched-arm hub molecule;
q is from about 2 to about 100;
A at each occurrence is independently a compound of formula II
or a pharmaceutically acceptable salt thereof, wherein
J is selected from:
a) a group of formula (a):
wherein R31 is a covalent bond to the polymer moiety which optionally comprises a linker, or R31 is selected from the group consisting of \u2014H, R31\u2032, \u2014NH2, \u2014NHR31\u2032, \u2014N(R31\u2032)2, \u2014NC3-C6cyclic, \u2014OR31\u2032, and \u2014SR31\u2032, wherein each R31\u2032 is independently an optionally substituted straight or branched C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl,
and R32 is a covalent bond to the polymer moiety which optionally comprises a linker, or R32 is selected from the group consisting of \u2014H, \u2014NO2, haloalkyl, and \u2014N(MR41)R42 wherein M is a covalent bond, \u2014C(O)\u2014 or \u2014SO2\u2014, and R41 is R41\u2032, N(R41\u2032)2, or \u2014OR41\u2032,
wherein each R41\u2032 is independently hydrogen, an optionally substituted straight or branched C1-C6alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or an optionally substituted heteroaryl, wherein optional substitutions are halide, C1-C6alkyl, or \u2014OC1-C6alkyl,
and R42 is hydrogen, R41\u2032, alkynyl, or substituted alkynyl; and
b) a group of formula (b):
wherein R is selected from the group consisting of a hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
Ar1 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar1;
Ar2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkylamino, and substituted alkylamino, wherein Ar2 is optionally covalently bound to the polymer moiety and wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar2;
X is selected from the group consisting of \u2014NR1\u2014, \u2014O\u2014, \u2014S\u2014, \u2014SO\u2014, \u2014SO2 and optionally substituted \u2014CH2\u2014 which is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety;
where R1 is selected from the group consisting of hydrogen and alkyl;
T is selected from:
a) a group of formula (c)
wherein Y is selected from the group consisting of \u2014O\u2014 and \u2014NR1\u2014 wherein R1 is selected from the group consisting of hydrogen and alkyl;
W is selected from the group consisting of a covalent bond to a polymer moiety which optionally comprises a linker and \u2014NR2R3 wherein R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and where R2 and R3, together with the nitrogen atom bound thereto, form a heterocyclic ring or a substituted heterocyclic ring wherein each of alkyl, substituted alkyl, heterocyclic and substituted heterocyclic is optionally covalently bound to a polymer moiety which further optionally comprises a linker;
m is an integer equal to 0, 1 or 2;
n is an integer equal to 0, 1 or 2; and
b) a group of formula (d)
wherein G is an optionally substituted aryl or optionally substituted heteroaryl 5 or 6 membered ring containing 0 to 3 nitrogens, wherein said aryl or heteroaryl optionally further comprises a covalent bond to a polymer moiety which optionally comprises a linker;
R6 is a covalent bond to a polymer moiety which optionally comprises a linker, or R6 is \u2014H, alkyl, substituted alkyl, or \u2014CH2C(O)R17, wherein R17 is \u2014OH, \u2014OR18, or \u2014NHR18, wherein R18 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R55 is \u2014OH or a hydrolyzable ester, or R55 forms a hydrolyzable polymer ester with the polymer moiety, optionally through a linker;
provided that:
A. at least one of J, R55, and T contains a covalent bond to the polymer moiety;
B. when X is \u2014O\u2014, then m is two; and
C. the conjugate of formula I has a molecular weight of no more than about 80,000.
2. The conjugate according to claim 1, wherein only one of J, R55 and T contains a covalent bond to a polymer moiety.
3. The conjugate according to claim 1, wherein n is 2, R at each occurrence is C1-C3 alkyl, and both R groups are on the same carbon.
4. The conjugate according to claim 1, wherein, q is an integer of from 2 to about 20.
5. The conjugate according to claim 1, wherein q is an integer of from 2 to about 8.
6. (canceled)
7. The conjugate according to claim 1, wherein A at each occurrence is independently a compound of formula IIb:
or a pharmaceutically acceptable salt thereof.
8. The conjugate according to claim 1, wherein A at each occurrence is independently a compound of IIc:
or a pharmaceutically acceptable salt thereof.
9-10. (canceled)
11. The conjugate according to claim 1, wherein A at each occurrence is independently a compound of formula IIf:
or a pharmaceutically acceptable salt thereof, wherein
R4 is covalently bound to a polymer moiety which optionally comprises a linker;
R5 is selected from the group consisting of alkyl and substituted alkyl; and
Ar3 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl.
12-14. (canceled)
15. The conjugate according to claim 14 wherein m is 1, X is S, and R at each occurrence is independently selected from hydroxyl, alkyloxy, alkyl, or a covalent bond to the polymer moiety.
16. The conjugate according to claim 15 wherein n is 2, and Rat both occurrences is methyl.
17. The conjugate according to claim 1, wherein A at each occurrence is independently a compound of formula IIj below:
or a pharmaceutically acceptable salt thereof.
18-19. (canceled)
20. The conjugate according to claim 17 wherein G is pyridinyl, R31 is hydrogen or dialkylamino, and R32 is sulfonamide, amide, or urea.
21. The conjugate according to claim 1, wherein A and B are as shown below:
B Moieties
A Moieties
\u2014C(O)O(CH2CH2O)pC(O)\u2014
Z
\u2014C(O)O(CH2CH2O)pC(O)\u2014
Z
\u2014C(O)O(CH2CH2O)pC(O)\u2014
ZZ (total Mw of conjugate is about 42,000)
ZZ (total Mw of conjugate is about 42,000)
ZZZ (total Mw of conjugate is about 41,000)
wherein
Z is
ZZ is
\u2003and
ZZZ is
where the sum of all p’s is from 100 to 1360.
22. A conjugate according to claim 1, selected from the group consisting of:
and a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a conjugate according to claim 1 or mixtures thereof.
24-31. (canceled)
32. A method for treating a disease state caused or exacerbated at least in part by alpha 4 integrin-mediated leukocyte binding in a patient, which method comprises administering an effective amount of a conjugate according to claim 1.
33-37. (canceled)
38. The method of claim 32 wherein the disease state is multiple sclerosis, meningitis, encephalitis, stroke, and other cerebral traumas
39. The method of claim 32 wherein the disease state is multiple sclerosis.
40-48. (canceled)
49. A pharmaceutical composition comprising a conjugate according to claim 1 in combination with an \u03b14\u03b27 inhibitor.
50. (canceled)